Development of a new analog of SGK1 inhibitor and its evaluation as a therapeutic molecule of colorectal cancer

Abstract

Colorectal cancer (CRC) is one of the most leading causes of cancer-related death worldwide. The serum and glucocorticoid inducible kinase SGK1 is highly expressed and involved in several tumors. GSK650394, a SGK1 inhibitor, has been proved to be effective in impeding tumor growth in <i>vitro</i>. In this study, we developed a novel analog of GSK650394, and evaluated its effects on CRC cells and tumor growth both in <i>vitro</i> and in <i>vivo</i>. HCT116 cells were treated with a concentration gradient of new developed compounds and cholecystokinin octapeptide (CCK-8) assay was used to calculate the IC50 value of every analog. Cell proliferation analysis was estimated from EdU staining and flow cytometry in <i>vitro</i>, and immunohistochemistry of Ki67 and PCNA in <i>vivo</i>. Cell migration analysis was examined using the transwell assay. In <i>vivo</i> tumor growth was determined in athymic nude mice by injecting the HCT116 cells in the subcutaneous tissue, followed by the injection of QGY-5-114-A. We found that new developed GSK650394 analog QGY-5-114-A has lower IC50 value, and treatment with QGY-5-114-A significantly inhibited CRC cell proliferation and migration in <i>vitro</i>. Besides that, colonic tumor growth was also dramatically restricted by QGY-5-114-A in <i>vivo</i>. In conclusion, pharmacological treatment with QGY-5-114-A impedes CRC tumor cell proliferation, migration and tumor growth.